Pak J Ophthalmol. 2020, Vol. 36 (2): 96-102 96 ORIGINAL ARTICLE Comparison of High Intensity Accelerated Corneal Cross Linking Protocols in Treatment of Progressive Keratoconus Bushra Akbar 1 , Imran Basit 2 , Amjad Akram 3 , Maham Zahid 4 1,2 Armed Forces Institute of Ophthalmology, Rawalpindi. 3 Combined Military Hospital (CMH), Kharian 4 National University of Medical Sciences (NUMS), Rawalpindi – Pakistan ABSTRACT Purpose: To compare the safety and efficacy of Accelerated Corneal Cross Linking (AXL) protocols, 9 mW/cm 2 for 10 min with 18 mW/cm 2 for 5 min in terms of refractive and topographic keratometric indices in patients with progressive Keratoconus. Study Design: Quasi experimental study. Place and Duration of Study: Armed Forces Institute of Ophthalmology, Rawalpindi Pakistan, from Nov 2016 to Jun 2018. Methods: Sixty eyes, 30 in each group, of 55 consecutive patients diagnosed with progressive keratoconus were enrolled through convenience sampling and were subjected to AXL with irradiance protocols of 18 mWatt/cm 2 for 5 minutes in group 1 and 9 mW/cm 2 for 10 minutes in group 2. All patients underwent a comprehensive ophthalmic examination at baseline and postoperative follow up visits at 3, 6, 12 and 18 months. Primary outcome parameter was disease stability defined as increase in maximum keratometry over baseline K max of no more than 1 diopter at 1 year after AXL. Statistical analysis of data was performed with IBM SPSS software (version 20.0 SPSS). P value of < 0.05 was considered as statistically significant. Results: Disease stability was 96 % in each group. At the final time point of 18 months, group 2 (AXL 9 mm watt/cm 2 for 10 min) was superior as compared to group 1 (AXL 18 mm watt/cm 2 for 5 min) in terms of flattening of steep and sim K (p = 0.007, 0.023 respectively). Conclusion: The two AXL protocols are safe and appear to show comparable efficacy in disease stability. They can be used alternatively in the treatment of progressive keratoconus. Key Words: Corneal Cross Linking, Keratoconus, Ultraviolet A, Accelerated Corneal Cross Linking. How to Cite this Article: Akbar B, Basit I, Akram A, Zahid M. Comparison of High Intensity Accelerated Corneal Cross Linking Protocols in Treatment of Progressive Keratoconus. Pak J Ophthalmol. 2020, 36 (2): 96-102. Doi: 10.36351/pjo.v36i2.976 INTRODUCTION High intensity Accelerated corneal collagen cross Correspondence: Bushra Akbar Armed Forces Institute of Ophthalmology, Rawalpindi– Email:dr.bushra.akbar@gmail.com Received: January 2, 2020 Accepted: March 5, 2020 linking protocols (AXL) with optimized beam profiles have been new options in treatment armamentarium of progressive keratoconus. AXL protocols are in accordance with Bunsen-roscoe law of chemical reciprocity that states “same photochemical effect can be achieved by reducing the irradiation interval, provided that the total energy level is kept constant by a corresponding increase in irradiation intensity.” 1 mailto:dr.bushra.akbar@gmail.com Bushra Akbar, et al 97 Pak J Ophthalmol. 2020, Vol. 36 (2): 96-102 The classical CXL Dresden protocol included debridement of the corneal epithelium in the central 7 to 9 mm area and a pre-soak of 30-minute, with riboflavin-5-phosphate and 20% dextran. It was followed by UVA irradiance of 3 mW/cm2 (365nm, total energy 5.4j/cm 2 ) for 30 minutes. 2 AXL protocols incorporated a fraction of time of Dresden protocol, with a proportionate increase in irradiation intensity in order to achieve total energy levels of 5.4 j/cm 2 equivalent to that proposed by Dresden classical protocol i.e.9 mW/cm 2 for 10 minutes, 18m W/cm 2 for 5 minutes and 30m W/cm 2 for 3 minutes. 3 The reduced surgical time of AXL confers the benefit of increased patient and surgeon comfort, minimal corneal dehydration and a decreased risk of postoperative infection owing to less exposure of denuded corneal epithelium. 4 The same photochemical effect or photo- activated corneal covalent intra and interlamellar stromal cross linking achieved by AXL and conventional protocols promise comparable efficacy in terms of disease stabilization and a relative improvement in topographic keratometric indices and refractive profiles by augmenting the biomechanical strength of cornea. 3-5 Previous comparative clinical trials conducted with variable beam profiles, with different riboflavin solutions, in different populations have claimed safety and comparable efficacy of conventional protocol vs. AXL algorithms. 5-9 We aimed to directly compare the safety and efficacy of AXL protocols, 9 mw/cm 2 for 10 minutes with 18 mW/cm 2 for 5 minutes in terms of refractive and topographic keratometric indices, in patients with progressive keratoconus. METHODS This study was conducted at Armed Forces Institute of Ophthalmology, Rawalpindi Pakistan, from Nov 2016 to Jun 2018 after approval from Hospital ethical committee and, in accordance with tenets of declaration of Helsinki. Sixty eyes of 55 consecutive patients diagnosed with progressive keratoconus were enrolled in this study after obtaining an informed written consent. Thirty eyes, each were randomized to AXL with irradiance protocols of 18 mWatt/cm 2 for 5 minutes in group 1 and 9 mWatt/cm 2 for 10 minutes in group 2. Inclusion criteria were; clear cornea, age between 18 to 40 years, documented evidence or reported progression with reduced visual acuity by more than 0.50 Snellen lines, an increase in the spherical/cylinder refraction of more than 0.50 D, an increase in the maximum keratometry reading of more than 1 D and a reduction in CCT of more than 10 µm over the previous 12 months; documented on a minimum of 2 corneal topographies over a period of 6 months. Any active or previous ocular infections, corneal opacities, dry eyes, corneal pachymetry of less than 400 microns at thinnest point, previous CXL treatment or any ocular surgery, active autoimmune disorders, pregnancy and lactation were excluded from the study. All patients underwent a comprehensive ophthalmic examination at baseline and postoperative follow up visits at 3, 6, 12 and 18 months, which included UDVA (uncorrected distance visual acuity), CDVA (corrected distance visual acuity) (Snellen visual acuity converted to log MAR notation), slit lamp biomicroscopy, dual scheimpflug corneal topography (Galilie G4), pachymetry (Galilie G4), specular microscopy (Topcon sp-3000, USA) for endothelial cell density analysis and dilated fundus examination. Rigid gas permeable contact lenses were discontinued for three weeks and soft contact lens for at least two weeks prior to baseline evaluation. AXL was performed under topical anaesthesia 0.05% proparacaine hydrochloride (Alkaine), in both groups as a day care procedure. Standard preoperative preparation with 5% povidine iodine solution was done. Central 9 mm of epithelium was scraped off, followed by instillation of one drop of isotonic riboflavin (0.1% riboflavin (Vit B2), HPMC 1.1% (Peschke M, PESCHKE Trade GmbH) every 2 minutes for 20 minutes. Cornea with pachymetry of less than 400 microns after epithelium removal and isotonic riboflavin instillation were treated with hypotonic riboflavin drops Peschke H (PESCHKE Trade GmbH) one drop every 5 seconds till it reached 400 microns. Cornea was exposed to UVA light of 366-370 microns at a distance of 55 mm from the eye at an irradiance of 18 mW/cm 2 for 5 minutes in group 1 and 9 mWatt/cm 2 for 10 minutes in group 2, delivering a total energy of 5.4 joules/cm 2 (CCL VARIO 365, PESCHKE Trade GmbH, Huenenberg Switzerland) in both groups, with continued instillation of riboflavin drops every 2 minutes. A bandage contact lens (Interojo, Korea) was applied and removed on 7 th post- operative day, if epithelium had healed. Post operatively cyclopentolate 1% eye drops were advised 8 hourly for 3 days and moxifloxacin (Vigamox 0.05%, Alcon) for 2 weeks respectively. Topical steroids Flourometholone (FML 0.1%, Corneal Cross Linking in Treatment of Progressive Keratoconus Pak J Ophthalmol. 2020, Vol. 36 (2): 96-102 98 Allergen) were added after one week, if epithelium had healed and continued for 4 weeks along with topical lubricants hypromellose, dextran (Tear Natural II, Alcon). Primary outcome parameter was disease stability defined as increase in maximum keratometry over baseline Kmax of no more than 1 diopter at 1 year after AXL. Refractive outcome UDVA, CDVA, spherical equivalent SE, Refractive astigmatism, change in simulated K and steep K, corneal pachymetry (central corneal thickness) were additional outcome measures documented at 3, 6, 12 and 18 months post AXL test points. Statistical analysis of data was performed with IBM SPSS software (version 20.0 SPSS). p value of < 0.05 was considered as statistically significant. Normality of data was established utilizing Kolmogorov smirnov test. Within the groups, related two samples comparisons at multiple points were performed with one way repeated measure ANOVA for normally distributing data and Wilcoxon matched pairs test for non-normally distributing data. Between the group comparisons for normally distributing data was done with independent sample t test and Mann - Whitney U test was applied to non-normal distributions. RESULTS The mean age was 24.47 ± 4.90 years in AXL group 1 and 24.81 ± 6.39 in AXL group 2, with no statistically significant difference. Keratometric parameters (simulated K, steep K, Kmax), refractive data (UDVA, CDVA, refractive astigmatism, spherical equivalent SE) and pachymetry, central corneal thickness (CCT) were comparable at baseline between the two AXL groups (Table 1). The mean postoperative log MAR UDVA improved at test points of 6, 12 and 18 months in both AXL groups, however these differences were not statistically significant (p = 0.361 and p = 0.138 respectively) (Table 2 and 3). The mean postoperative log MAR CDVA significantly improved over mean preoperative value in both the groups (p = 0.020 and p = 0.020). However, the difference in post-operative log MAR UDVA and CDVA was not statistically significant between the AXL groups at any time point (p = 0.979, 0.700, 0.873, 0.125, 0.072, 0.171 respectively) (Table 4). The refractive Astigmatism and spherical equivalent SE showed significant reduction from baseline at all postoperative test points of 3, 6, 12 and 18 months in both groups (p < 0.05). Astigmatism reached significance in group 2 only at Table 1: Preoperative Comparison of Parameters. Parameters Accelerated CXL P value GP 1 (n = 30) GP 2 (n = 30) UCVA 0.75 ± 0.51 0.65 ± 0.58 0.486 CDVA 0.37 ± 0.27 0.26 ± 0.22 0.090 SE -6.05 V 3.08 -6.2 ± 2.85 0.781 Ast -4.15 ± 1.69 -3.81 ± 5.52 0.540 Steep K 50.4 ± 3.72 49.6 ± 3.53 0.404 Sim K 48.37 ± 2.96 47.8 ± 2.92 0.379 b K max 53.97 ± 4.29 53.63 ± 4.80 0.774 CCT 471.20 ± 36.91 479 ± 37.7 0.442 b ECD 2566.19 ± 428.61 2516.88 ± 343.85 0.781 a Independent samples T-test, b Mann-Whitney U test *P<0.05. UCVA = Uncorrected distance Visual acuity, CDVA = corrected distance visual acuity, SE = Spherical equivalent, Ast = Refractive astigmatism, Steep K = Steep keratometry, Sim K = Simulated keratometry, Kmax = Maximum or Apex Keratometry, CCT=central corneal thickness 12 and 18 months follow-up (p = 0.000, 0.000) (Tables 2, 3). The change in SE and Astigmatism did not differ between two groups (Table 4). Disease stability that was the primary outcome measure was 96% in each group in present study. Similar trend of significant flattening of Kmax, sim K, steep K was observed in each group (p < 0.05) against baseline indices. At 6 and 12 months follow up, no significant differences in keratometric parameters Kmax, sim K, and steep K were ascertained comparing both procedures. At the final time point of 18 months, group 2 (AXL 9 mWatt/cm 2 for 10 minutes) was superior as compared to group 1 (AXL 18mWatt/cm 2 for 5 minutes) in terms of flattening of steep and sim K (p = 0.007, 0.023 respectively) and Kmax, that barely missed statistical significance (Table 4). CCT in group 2 showed reduction of 23.16 ± 21.77 microns in group 1 and 25.06 ± 28.18 in group 2 with no statistically significant difference at any follow-up between the groups (p = 0.855, 0.351,0.771 respectively) (Table 4). Intra-group analysis showed significant reduction in endothelial cell count at the end of six, twelve and eighteen months in all groups (p < 0.05 in all groups). However, between the groups, the reduction in endothelial cells was not statistically significant at any time point. In group 2, one eye had a mild stromal haze that resolved with corticosteroid treatment by 6 weeks. No incidence of corneal endothelial de-compensation or any other adverse effect was recorded in any treatment Bushra Akbar, et al 99 Pak J Ophthalmol. 2020, Vol. 36 (2): 96-102 Table 2: Comparison of Pre and Post-operative refractive and topographical measurements in AXL Group 1 - (18 mWatt/cm 2 for 5 min). Parameters Postoperative Follow-up Time Period P value Pre-operative (n = 30) 3 Months (n = 30) 6 Months (n = 30) 12 Months (n = 30) 18 Months (n = 30) UCVA 0.75 ± 0.51 0.71 ± 0.47 0.73 ± 0.46 0.67 ± 0.45 0.65 ± 0.43 0.361 CDVA 0.37 ± 0.27 0.34 ± 0.20 0.38 ± 0.25 0.32 ± 0.27 0.31 ± 0.27 0.020* SE -6.05 ±3.08 -5.05 ± 2.67 -4.12 ± 2.57 -4.66 ± 3.03 -4.60 ± 2.96 0.000* Ast -4.15 ± 1.69 -3.79 ± 1.61 -3.48 ± 1.11 -3.03 ± 1.20 -2.97 ± 1.18 0.000* Steep K 50.48 ± 3.72 49.95 ± 3.76 49.71 ± 3.67 49.31 ± 3.62 49.18 ± 3.59 0.000* Sim K 48.37 ± 2.96 48.02 ± 3.20 48.09 ± 3.18 47.64 ± 3.18 47.57 ± 3.20 0.001* K max 53.97 ± 4.29 53.45 ± 4.09 53.26 ± 3.74 52.22 ± 3.92 52.27 ± 3.94 0.000* CCT 471.20 ± 36.91 452.60 ± 43.57 456.96 ± 44.38 447.40 ± 43.24 446.50 ± 44.25 0.000* One-way ANOVA repeated measures test, *P < 0.05. AXL = Accelerated CXL, UCVA = Visual acuity, CDVA = Corrected distance visual acuity, SE = Spherical equivalent, Ast = Refractive astigmatism, Steep K = Steep keratometry, Sim K = Simulated keratometry, Kmax = Maximum or Apex Keratometry, CCT=central corneal thickness Table 3: Comparison of Pre and Post-operative refractive and topographical measurements in AXL Group 2 - (9 mwatt/cm 2 for 10 min). Parameters Postoperative Follow-up Time Period P value Preoperative (n = 30) 3 Months (n = 30) 6 Months (n = 30) 1 Year (n = 30) 18 Months (n = 30) UCVA 0.65 ± 0.58 0.73 ± 0.49 0.62 ± 0.53 0.60 ± 0.51 0.56 ± 0.45 0.138 CDVA 0.26 ± 0.22 0.27 ± 0.20 0.32 ± 0.25 0.28 ± 0.27 0.26 ± 0.25 0.022* SE -6.27 ± 2.85 -5.68 ± 2.80 -4.52 ± 2.18 -4.96 ± 2.84 -4.27 ± 2.25 0.000* Ast -3.81 ± 2.52 -3.98 ± 1.87 -3.68 ± 1.49 -2.62 ± 2.32 -2.50 ± 1.26 0.000* Steep K 49.69 ± 3.53 49.17 ± 3.44 48.78 ± 3.49 48.40 ± 3.47 47.56 ± 3.41 0.000* Sim K 47.84 ± 2.92 47.36 ± 2.94 47.10 ± 3.09 46.72 ± 2.95 46.07 ± 3.00 0.000* K max 53.63 ± 4.80 52.95 ± 4.37 52.94 ± 4.39 51.70 ± 4.38 50.92 ± 4.33 0.001* CCT 479.80 ± 37.75 455.10 ± 44.72 467.26 ± 45.97 461.93 ± 47.99 454.73 ± 47.05 0.000* ANOVA repeated measures test, *P < 0.05. AXL = Accelerated CXL, UCVA = Uncorrected distance Visual acuity, CDVA = Corrected distance visual acuity, SE = Spherical equivalent, Ast = Refractive astigmatism, Steep K = Steep keratometry, Sim K = Simulated keratometry, Kmax = Maximum or Apex Keratometry, CCT =central corneal thickness Table 4: Comparison of Post-operative changes in refractive data, keratometry and pachymetry between two study groups. Parameters Follow-up Time period G r o u p c o m p a r is o n A t 6 m o n th s (P 1 v a lu e ) G r o u p c o m p a r is o n A t 1 2 m o n th s (p 2 v a lu e ) G r o u p c o m p a r is o n A t 1 8 m o n th s (p 3 v a lu e ) Group 1 Group 2 6 Months (n = 30) 12 Months (n = 30) 18 Months (n = 30) 6 Months (n = 30) 12 Months (n = 30) 18 Months (n = 30) UCVA -0.29 ± 0.27 -0.82 ± 0.29 -0.82 ± 0.29 -0.31 ± 0.40 -0.05 ± 0.28 -0.94 ± 0.29 0.979 0.700 0.873 CDVA 0.11 ± 0.15 -0.045 ± 1.56 -0.45 ± 0.15 0.06 ± 0.12 0.22 ± 0.12 0.01 ± 0.11 0.125 0.072 0.171 SE 1.93 ± 3.29 1.39 ± 1.04 -5.42 ± 3.46 1.74 ± 2.45 1.30 ± 1.54 -4.93 ± 2.69 0.803 0.793 0.548 Ast 0.67 ± 1.02 1.12 ± 0.99 1.12 ± 0.99 0.12 ± 1.98 1.18 ± 3.25 1.31 ± 2.10 0.189 0.922 0.660 Steep K -0.77 ± 1.10 -0.77 ± 1.10 -1.16 ± 1.40 -0.91 ± 1.68 -0.91 ± 1.68 -2.13 ± 1.77 0.694 0.694 0.023* Sim K -0.28 ± 1.15 -0.73 ± 1.44 -0.73 ± 1.44 -0.73 ± 1.13 1.11 ± 1.30 -1.77 ± 1.42 0.130 0.283 0.007* K max -0.70 ± 2.04 -1.74 ± 2.34 -1.70 ± 2.48 -0.68 ± 1.32 -1.93 ± 1.51 -2.71 ± 1.43 0.967 0.723 0.058 CCT -14.23 ± 35.45 -23.80 ± 21.99 -23.16 ± 21.77 -12.53 ± 36.27 -17.86 ± 26.62 -25.06 ± 28.18 0.855 0.351 0.771 ECD -3.66 ± 6.00 -4.16 ± 6.28 -4.16 ± 6.28 -3.52 ± 5.99 -4.01 ± 6.30 -3.44 ± 6.58 0.926 0.929 0.670 Independent samples T test. *P < 0.05. AXL = Accelerated CXL, UCVA = Visual acuity, CDVA = Corrected distance visual acuity, SE = Spherical equivalent, Ast = Refractive astigmatism, Steep K = Steep keratometry, Sim K = Simulated keratometry, Kmax = Maximu m or Apex Keratometry, CCT =central corneal thickness, ECD = Endothelial cell count Corneal Cross Linking in Treatment of Progressive Keratoconus Pak J Ophthalmol. 2020, Vol. 36 (2): 96-102 100 Table 5: Previous Clinical Trials of AXL. Study Study Design Conventional Cross Linking Accelerated Cross Linking Follow-up (Months) Findings N Protocol/ Platform N Protocol/Platform Cinar et al. 2014 7 Prospective comparative case series 13 3 mW/cm 2 for 30 mins 13 9mW/cm 2 for 10 mins 6 Comparable visual and refractive results, decrease in Km and Kmax in both groups Hashemi et al. 2015 8 Prospective randomized comparative case series 31 3 mW/cm 2 for 30 mins UV-X 31 18mW/cm 2 for 5 mins UV-X 6 Comparable visual acuity, refractive, keratometric and biomechanical outcomes Hashemi et al. 2015 9 Prospective randomized 31 18 mW/cm 2 for 5 mins UV-X 31 3mW/cm 2 for 30 mins UV-X 18 Comparable visual acuity, refractive, keratometric and biomechanical outcomes Chow et al. 2015 10 Prospective comparative case series 19 3 mW/cm 2 for 30 mins UV-X 19 18mW/cm 2 for 5 mins CCL-VARIO 12 Comparable visual acuity and refractive outcomes. More topographic flattening in the conventional group compared to accelerated group Shetty et al. 2015 11 Prospective randomized interventional study 36 3 mW/cm 2 for 30 mins Avedro KXL 36 9mW/cm 2 for 10 mins 12 Conventional group and accelerated groups with irradiance of 9mW/cm2 and 18mW/cm 2 showed better visual, refractive and tomographic 33 18mW/cm 2 for 5 mins Cummings et al 2016 12 Retrospective interventional study 66 3mW/cm 2 for 30 mins 36 9mW/cm 2 for 10 mins 12 Accelerated corneal CXL is effective in stabilizing topographic parameters better after 12 months 9mW/cm 2 Yildrim et al 2017 13 prospective comparative study 74 18mW/cm 2 for 5 mins 72 30mW/cm 2 for 3 mins 12 Comparable visual acuity, refractive, keratometric UCVA = Uncorrected distance Visual acuity, CDVA = Corrected distance visual acuity, SE = Spherical equivalent, Ast = Refractive astigmatism, Steep K = Steep keratometry, Sim K = Simulated keratometry, Kmax = Maximum or Apex Keratometry, CCT = Central corneal thickness group during follow-up. One eye (4%) in each group exhibited continued ectatic progression in terms of increase in Kmax of more than 1 dioptre. DISCUSSION The promising effects of AXL in halting disease progression by augmenting corneal strength and halving the surgical time with increased patient comfort have excited ophthalmologic researchers. Modified higher UVA irradiation intensity protocols with different time settings utilizing variable riboflavin solutions, soak time and CXL devices have been tested with the aim of achieving a short and equally effective procedure to date. 3-13 In this particular study, both AXL showed equivalent improvement in UDVA, CDVA and topographic indices at 3, 6, 12 and 18 months follow-up except for flattening of keratometry (sim K, Steep K) that was significantly superior in AXL group 2 (p < 0.007, 0.023) at 18 months follow- up. Comparable clinical stabilization of disease (96%) was achieved with optimum safety in each group. Failure rate of 4% in terms of continued progression, with no other adverse effects were documented in our study. Significant improvements in our study in UDVA, CDVA along with reduction in SE and Ast at 6 and 12 months over baseline were consistent with refractive outcomes of prospective well designed interventional trials that recruited one arm of cohort to receive CXL irradiance protocol similar to our study. 6,11,12 Hashemi et al 8,9 and Al-Nawaeiseh et al 14 in contrast to our results reported no significant improvements in refractive parameters at 12 months in patient receiving 5 minutes accelerated protocol. CXL alone without excimer laser is not considered a refractive procedure Bushra Akbar, et al 101 Pak J Ophthalmol. 2020, Vol. 36 (2): 96-102 albeit, the effect on refractive parameters in different studies may be attributed to variable grades of keratoconus and associated difficult non repeatable subjective manifest refractions due to distorted multi focal optics of ectatic steep corneas. 12 In present study, AXL groups demonstrated significant trend of flattening of keratometric indices Kmax, steep K, sim K within groups, with no superiority between the groups, except for sim K and steep K at 18 months follow-up. Although K max only just missed statistical significance at 18 months, a marked flattening of 2.7D was attained with 9 mWatt/cm 2 for 10 minutes regimen as compared to 1.5D in group 1. This trend of decrease in keratometric values was generally in accordance with results of previous studies of accelerated protocols. Shetty et al 11 in a prospective interventional study on 138 keratoconic eyes, with randomization at radiance of 3, 9, 18 or 30 mWatt/cm 2 found that cross linking, flattening effect was abridged in higher irradiance and shorter duration treatments, in conformation with our results. However, the disease stability with AXL in each group in our study with no further corneal steeping at a long term follow up of 18 months is a significant clinical finding, even if it misses statistical significance between the groups. The decrease in CCT is an indirect marker of efficacy of AXL, confirming compactness of collagen fibrils, apoptosis of stromal keratocytes and improved biomechanical stability. 8,9,15 Hashemi et al 8,9 identified a statistically significant decrease in CCT at 18 months following AXL with 18 mWatt/cm 2 for 5minutes. We also observed a parallel decrease in CCT for both groups, without significance between the protocols at 18 months. Significant decrease in thinnest pachymetry was also reported for AXL 9 mWatt/cm 2 in comparison against conventional CXL in literature. 12,16,17 We lack the evidence of AXL induced structural change in anterior corneal stroma as anterior segment optical coherence tomography was not done in our study to assess the depth of demarcation line. In addition to this, the major limitation of this study was a relatively small sample size. We intend to follow our patients and publish our long term results to further validate efficacy of our procedures. We had 4% eyes in each group that experienced ectatic progression at 12 and 18 months, in terms of increase in Kmax, with no incidence of sterile infiltrates, persistent corneal haze and damage or loss of endothelial cells succumbing to corneal endothelial decompensation, akin to previous AXL trials. 12,18,19,20 CONCLUSION AXL protocols are safe and comparable in disease stability, and change in refractive parameters and topographic indices in progressive Keratoconus. These two modified high intensity protocols may be recommended alternatively in treatment of progressive keratoconus, considered fit for epithelium off CXL. ACKNOWLEDGEMENTS Mr Kashif Siddique, King Salman armed forces hospital, KSA Academic affairs (Research Unit) for helping in data analysis. Miss Paree Chera, Ex Optometrist, Armed forces institute of ophthalmology for helping in collection of data. Ethical Approval The study was approved by the Institutional review board/Ethical review board. 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J Cataract Refract Surg. 2014 Dec; 40 (12): 1971-1979. Authors’ Designation and Contribution Bushra Akbar; Registrar: Study design, analysis of data, manuscript drafting and critical revision of final draft. Imran Basit; Assistant Professor: Study design, analysis of data, manuscript drafting and critical revision of final draft. Amjad Akram; Research Advisor: Critical revision of manuscript, final approval of draft for publication. Maham Zahid; Research Associate: Data collection, analysis of data, interpretation of data, manuscript drafting and final approval of draft. .…  …. https://doi.org/10.1016/j.jcrs.2007.12.039 https://doi.org/10.1016/j.ajo.2015.05.019 https://doi.org/10.1016/j.jcrs.2009.03.035